The cell division processes required for bacterial
life

Abstract

The
smallest living building block of life, the cell,
is enormously complex, and a great number of
its mechanisms are irreducibly complex. Few theories
have been proposed explaining how irreducibly
complex mechanisms could have evolved by Darwinian
natural selection. It could be argued that given
enough time a simple reproducing population of
living ìprotocellsî could have provided a format
for the evolution of complex mechanisms. However,
even in ìsimpleî bacteria, the most basic cell
functions display irreducibly complex mechanismsófor
instance, cell division. This article considers
the origin of an irreducibly complex cell division
apparatus and contrasts protocell theory with
intelligent design theory.

"The
only life we know for certain is cellular....."

Harold J. Morowitz

Protocell
theory is a popular theory often proposed to
explain how biochemical complexity arose in living
cells by completely natural, evolutionary processes.
The theory postulates that the complex cells
we observe today evolved gradually from simpler
protocells via natural selection. For example,
Harold Morowitz has suggested that the original
protocells were unstable and prone to self-destruction;
but through the continual formation of billions
of protocells over millions of years, eventually
a stable, more advanced, protocell formed (Morowitz,
1992).

In
contrast to protocell theory, intelligent design
theory postulates that some biochemical mechanisms
within cells are irreducibly complex, which implies
that they are not products of any gradual, naturalistic
process of formation. For example, many cell
mechanisms resemble preassembled machines containing
interdependent parts that work together to perform
a cell function. Since all the co-dependent parts
must be present before the mechanism is capable
of function at all, it is unlikely that the mechanism
evolved by any gradual process, but instead appears
to have been designed.

Examples
of irreducibly complex biological systems have
been documented by biochemist Michael Behe in
Darwinís Black Box (Behe, 1996). Behe
defines irreducible complexity as ìa single system
of several well matched, interacting parts that
contribute to the basic function, where the removal
of any one of the parts causes the system to
effectively cease functioning.î As one of several
examples, Behe cites the bacterial flagellum,
a whip-like cell appendage that has a complex
motor apparatus at its base. How did such a complex
structure evolve in what is often described as
a ìsimpleî cell? Protocell theorists propose
that the bacterial flagellum evolved gradually
by natural selection (Loomis, 1984), implying
that such complex mechanisms are late developments
in the evolution of bacteria and would not have
been present in early protocells.

If,
however, the protocell is a self-reproducing
cell, as the theory suggests, then several essential
cell functions that appear to be complex in contemporary
cells would have to be present even in the early
protocell. For instance, a cell division mechanism
would be essential even in early stages of protocell
evolution. The impression given in many biology
textbooks is that cell division is a simple process.
However, upon close examination it becomes clear
that cell division even in bacteria is a complex
cellular process. This raises several questions
concerning protocell theory. For instance, how
did a simpler cell division mechanism function?
How did it lead to the complex mechanism we observe
today? Are any remnants of a simpler cell division
process evident in cells today? Is the cell division
process irreducibly complex?

The
existence of an irreducibly complex cell division
process would present two problems for protocell
theory. First, it would require the theory to
explain the origin of a protocell that must possess,
at a minimum, an irreducibly complex cell division
process for survival. Second, if a protocell
is capable of surviving with a simple cell division
process, how does natural selection lead to a
more complex, indeed an irreducibly complex,
cell division mechanism?

In
considering these questions, I will examine cell
division in bacteria. There is general agreement
among biologists that bacteria represent a late
protocell, or at least an evolutionary link between
a simpler protocell and eukaryotes, based on
the fact that bacteria appear to be simple cells,
both morphologically and genetically, compared
with eukaryotes. Bacteria are also well adapted
to independent unicellular life and hostile environments,
conditions postulated to exist on the early earth.
However, the assumption that bacteria are simple
is itself open to question, as we shall see.
I will focus on one primary question: Is there
a minimum set of reactions a bacterium must possess
to divide and reproduce, and, if so, are these
mechanisms irreducibly complex?

The
basics of cell division

Letís
begin by listing the essential processes a bacterium
must possess to reproduce effectively. For the
sake of simplicity, we will ignore for the time
being the requirement for energy in the form
of ATP and its biochemical production in the
cell.

DNA
replication. Without duplication of the molecule
that contains the genetic code, life cannot
continue.

Cytokinesis.
This involves division of the cell housing,
which includes the cytoplasm and membrane components.
The cell housing must be manufactured and assembled
before the cell divides, otherwise the
newly replicated cells would continually reduce
in size with each division.

Protein
synthesis. The cell must make or acquire proteins
since DNA replication and membrane production
both require enzymatic processes.

DNA
segregation. The cell must have a way to partition
its DNA equally among the new offspring.

Coordination
between DNA replication and cytokinesis. The
two basic stepsóDNA replication and cytokinesesómust
be coordinated, otherwise the cell cytoplasm
and membrane could divide before the DNA replicates,
leading to anucleated, nonviable offspring
or cells with multiple chromosomes (polyploidy).

The
common link among all the processes mentioned
above is the need for proteins. In fact, if protein
synthesis is inhibited, cell division ceases
(Lewin, 1997). Therefore, unless there is a source
of pre-manufactured proteins that can be transported
into the cell, the cell itself must contain a
protein synthesis process. Even in bacteria,
protein synthesis is a highly complex and regulated
process, involving many proteins and machine-like
protein complexes. More than 200 hundred proteins
involved in this process have been identified
in the bacterium Escherichia coli (E.coli)
(Javor, 1998). Without this protein synthesis
machinery, bacteria would not be able to divide
(nor even keep the cellís ìhouseî in order).1

Is
cell division irreducibly complex?

Letís
now consider our central question: Are the complex
biochemical processes that control cell division
representative of a minimal set of reactions
that the cell requires for life, and are they
irreducibly complex? There is good evidence to
suggest that the process of cell division is
indeed irreducibly complex, for the steps involved
are interdependent and highly coordinated. For
example, crucial steps such as DNA transcription
require proteins (see Figure 1)ówhile protein
synthesis in turn is dependent upon transcription.
Moreover, evidence suggests that the processes
involved in cell division are highly regulated
and coordinated in a sequential fashion. For
instance, in bacteria, cytokinesis does not proceed
until DNA replication is complete, so that the
DNA is precisely partitioned into the developing
daughter cells. Each process itself is complex
and if any one of the processes is inhibited,
cell division ceases. This interdependence fits
the criteria of an irreducibly complex system.

Figure
1. Relationship between some of the basic
biochemical processes that are required for life
and cell division. Transcription and translation
are processes that are involved in making proteins
by deciphering the genetic code (DNA). However,
proteins are required for both the transcription
and translation processes, as well as for DNA
replication and cytokinesis. Note that proteins
play a vital role in each cell process and serve
as the major interconnecting link between each
process. Cell division is a protein-dependent
mechanism.

Does
this arrangement also represent a minimal system
that must be present in all cells, including
any hypothetical protocell? Or could it have
evolved gradually? Letís consider the possible
gradual derivation of the cell division apparatus
in the protocell.

Cell
division and the protocell

One
of the more popular theories of protocell evolution,
presented in biology textbooks, involves the
encapsulation of the basic processes of biopolymer
synthesis in a membrane (Cooper, 1997). It is
then postulated that the protocell began to divide
by a simple mechanism. In other words, it is
assumed that all the cell functions required
for life, perhaps even those required for cell
division, were pre-manufactured and pre-functioning
processes sequestered together by a cell membrane.
(One barrier to cell division that the early
protocell would encounter is that in an aqueous
environment there is a natural physical resistance
to the membrane disruption needed for cell division.
For the sake of discussion, we will assume that
the dividing protocell was in a membrane-disrupting
environment that promoted some type of membrane
blebing or stressing so that new cells could
bud or pinch off the protocell.)

There
are several fundamental problems with the encapsulation
theory. First, how does a cytokinesis process
develop before the membrane forms the cell? Cytokinesis
requires a membrane-enclosed cytoplasmic space
and could only develop after encapsulation. Yet
in that caseóif cytokinesis evolved only after
encapsulationóthen it would have to evolve rapidly,
otherwise the cell would not reproduce and its
long-term survival would be questionable. One
possible postulate is that the early cytokinesis
process was a much simpler process compared with
the complex cytokinesis mechanism observed in
bacteria today. That would imply, however, that
there was very little regulation or no coordination
between DNA replication and cytokinesis and other
cell systems, which in turn implies that the
division of the membrane and successful transfer
of genetic material was haphazard and inefficient.
The protocell would partition its DNA into new
daughter bacteria, and then divide, by random
uncoordinated processes.

Letís
examine some hypothetical protocell models that
involve cell division without coordination between
the processes of DNA replication, protein synthesis,
and cytokinesis. To keep the model simple we
will portray the early protocell as monoploidói.e.,
containing one strand of DNA (though some researchers
suggest that the early protocell may have been
polyploid, harboring short pieces of DNA).

In
contemporary bacteria, DNA replication precedes
cytokinesis so that a single cell momentarily
has what appear to be two copies of circular
DNA; thereafter the DNAs are partitioned into
two new daughter bacteria, resulting in two separate
daughter bacteria with one circular DNA molecule
each. If, however, in the early protocell there
was no coordination between cytokinesis and DNA
replication, we can predict two scenarios for
how early protocell division could have occurred:
either DNA replication occurred at a faster rate
than cytokinesis, or, conversely, cytokinesis
occurred at a faster rate than DNA replication.
If cytokinesis occurred at a faster rate, the
result would be the production of many anucleate,
nonviable bacteria. The parent cell would accumulate
DNA and become polyploid with the potential occasionally
to produce daughter bacteria containing DNA (see
Figure 2). Alternately, if DNA replication preceded
cytokinesis, then greater numbers of viable offspring
would be produced at a faster rate. However,
in this case once again DNA would accumulate
in some bacteria due to unequal partitioning,
leading to polyploidy. It is interesting to note
that a population of both monoploid and polyploid
bacteria seems to be a common outcome for all
the predicted protocell division scenarios.

Figure
2. Hypothetical model of protocell division.
In the protocell, DNA replication and cytokinesis
would not be coordinated. Therefore DNA replication
could occur faster or slower than cytokinesis.
This figure shows a potential outcome of cytokinesis
occurring at a faster rate than DNA replication.
Note that many non-viable, anucleate daughter
bacteria would be produced, as well as bacteria
that are monoploid or polyploid. An animated
version of this figure is available for viewing
at: http://www.cedarville.edu/dept/sm/jwf/division.htm.

Polyploidy:
The problem of a full house

Since
polyploidy is predicted to be a common outcome
of protocellular life, and it since is generally
detrimental to cellular life in contemporary
cells, it is important to consider its effects
on protocell evolution. Polyploidy would present
at least two major hurdles for the evolving protocell.
First, it would mean a diminished capacity for
natural selection of favorable traits. For instance,
Koch has calculated an upper limit for the number
DNA copies the protocell could reasonably contain
and still flourish. His upper limit for DNA is
based on the fact that favorable mutations would
be diluted in the ìselfishî protocell carrying
great numbers of chromosomes and duplicate genes
(Koch, 1984).

Another
problem that polyploid protocells would face
is regulation of cell volume. The cell volume
would eventually have to adjust to accommodate
the increase in DNA and a corresponding increase
in protein production. (In contemporary organisms
that successfully harbor polyploid cells, those
cells are larger than its typical cell.) How
does the protocell adjust its size if there is
no coordination between membrane events and biopolymer
production? Perhaps the cell could inhibit uncontrolled
DNA replication and protein accumulation by the
production of an inhibitor of gene expression.
But in that case, what would control the inhibitor
so that it would not inhibit gene expression
of all DNA, especially if the inhibitor is concentration-dependent
and is transferred to a daughter cell with fewer
DNA strands? We could postulate that an inhibitor
would require a complex mechanism to ensure that
gene expression from at least one DNA is not
inhibited.

Despite
these problems, is it possible that a viable
bacterium with either a single DNA chromosome
or several DNA chromosomes could be consistently
produced throughout these reproduction cycles?
Certain mathematical models show that this is
possible, though production of nonviable cells
would be common. It is also possible that this
stochastic cell division process would create
the condition we find in natureónamely, the continual
production of bacteria that contain only one
DNA molecule (monoploidy). However, the question
remains how the unregulated division process
of the protocell would lead to the highly organized
and controlled division process that we observe
in bacteria today.

The
clockwork of cell division

To
answer that question, we need to focus for a
moment on those highly organized and regulated
processes observed in the majority of bacteria
today. Biochemical analysis reveals a bacterial
cell division process that operates with remarkable
precision. For example, E.coli bacteria
replicate their DNA every 40 minutes (Lewin,
1997). In wild type E.coli, DNA replication
and cytokinesis each occur at fixed time intervals
(the latter takes 18 to 20 minutes), and the
entire cycle is repeated with clockwork-like
precision each time a bacterium divides. However,
E.coli exposed to favorable conditions
(when resources are plentiful) can divide as
fast as 18 minutes, because the cell can overlap
the fixed processes. That is, DNA replication
can begin twice before the cell membrane divides,
such that the new daughter bacteria receive DNA
that is in the process of being replicated.

What
is the signal for this increased rate of response?
The trigger mechanism is unknown, but what is
known is that bacterial cell division is coordinated
precisely with the increase in bacterial cell
mass. If the rate of cell growth is fast, the
cell division mechanism responds by cycling at
a faster rate. As a recent review article notes,
ìIt is surprising that genetics, which has been
a powerful tool in unraveling other regulatory
circuits, has not yet been exploited to elucidate
how E.coli regulates its massî (Vinella,
1995). One theory suggests that as the cell increases
its mass, it also increases the concentration
of an ìinitiatorî protein that triggers the cell
cycle. Even though it is not yet clear how such
an initiator may work, many of the events surrounding
the initiation of both DNA replication and cytokinesis
are being elucidated.

To
better understand how both of these processes
are coordinated and regulated during cell division,
letís take a look at what is known about the
initiation of both of these events.

Initiation
of DNA replication

The
goal of DNA replication in bacteria is the duplication
of a circular DNA strand. Once DNA replication
begins, the cell is committed to complete the
process. The primary player in DNA replication
is the DNA polymerase protein, which is a fairly
large and complex protein that works in coordination
with DNA to unwind proteins. Coordinating with
it is a specialized ring-clamp protein that can
literally glide up and down the DNA and help
keep the DNA polymerase tethered to the DNAóan
apparatus referred to as the replisome. How does
the DNA polymerase ìknowî when and where to assemble
the replisome?

Before
the polymerase can find its start site, two problems
must be solved: the DNA must unwind, and single-stranded
DNA must be exposed. The unwinding and stabilization
of single DNA strands involves an elaborate arrangement
of proteins called an initiation complex, which
assembles at a unique site on the DNA (see Figure
3). A protein designated DnaA is the most crucial
protein involved in the initiation complex and
it is found in many bacteria. DnaA recognizes
specific nucleotide sequences and binds to them
near a site on the DNA called the origin of replication.
Individual DnaA proteins also have the special
property of being able to bind to one another,
and they exploit this ability by forming a cluster
of up to 40 monomers, which causes the DNA to
bend around the cluster. The bending stresses
the structure of the double helix and several
regions that are rich in A-T base pairs open
up, exposing single strands of DNA. (A-T base
pairs are weaker than G-C base pairs). However,
the unwinding of the DNA causes tension in the
DNA double helix, because the entire bacterial
DNA chromosome is circular. This tension is relieved
by two other proteins present in the initiator
complex: DnaB and DnaC. This complex of DnaB
and DnaC is so large that it appears as a blob
when visualized with the aid of an electron microscope.
It is often referred to as the engine of initiation.

Figure
3. Initiation of DNA-replication in prokaryotes.
DnaA protein binds to repeated sequences on the
DNA near a site called the origin of replication.
These repeated sequences are conserved and are
called consensus sequences. The consensus sequences
that the DnaA protein recognizes are of two classes,
those containing nine nucleotides and those containing
thirteen. The self-association of the DnaA monomers
forms a cluster that causes the DNA to distort
and bend. The bending causes unwinding of the
DNA. The unwinding continues with the aid of
three other proteins, Helicase (DnaB), DnaC,
and gyrase. Single-stranded DNA is also stabilized
by a protein called SSB (not shown). (Based on
Figure 15.18 in Lewin, 1997.)

The
initiator engine eventually displaces the DnaA
and promotes the continued unwinding of DNA through
the specific action of DnaB, which is a helicase.
Helicases are ATP-dependent enzymes that break
hydrogen bonds and can unwind DNA at a rate of
500-1000 base pairs per second. Helicases are
classified as motor proteins, which are enzymes
that convert chemical energy into physical movement.
E.coli has 12 distinct helicases. The DnaB helicase
works in conjunction with another protein called
gyrase, which is part of another family of proteins
essential for cellular life called topoisomerases.
Gyrase has the remarkable ability to cut, unwind,
and then rejoin DNA strands, relieving the tension
created by the helicase-induced unwinding.

The
DnaB helicase creates an interesting problem.
The unwound single-stranded DNA is much less
stable than the double-stranded form and it can
potentially bind to itself. Another protein called
single-stranded binding protein (SSB) binds to
the strands and stabilizes them. The SSB proteins
are required for replication, and a mutation
in the gene for their production is lethal.

It
certainly appears that several crucial factors
must be in place for successful initiation of
DNA replication, and moreover it appears that
they work together in an irreducibly complex
fashion.

A
possible objection to the conclusion of irreducible
complexity is that DNA replication can be performed
in a cell-free system by adding back just a few
components of the replication machinery. This
procedure known as PCR (polymerase chain reaction)
is a simple and powerful way to increase the
concentration of isolated DNA in the laboratory.
The procedure requires the use of DNA polymerase
but does not require DnaA, helicase, or gyrase.
One might conclude, therefore, that these components
are not needed and that DNA replication can be
achieved by a simpler, possibly non-irreducibly
complex mechanism.

However
this is not the case; the PCR reaction involves
procedural steps that essentially replace the
functions of the missing enzymes. For example,
high temperature is used in the PCR reaction
to unwind and ìunzipî the DNAóessentially replacing
the functions performed by the helicase and gyrase
enzymes. Thus the same functions are always required
for DNA replication, even if they are achieved
in different ways.

The
initiation of cytokinesis

Cytokinesis
involves the coordination of many interacting
components and must perform several major feats,
including the synthesis of the membrane and cytoplasmic
components required to create two bacteria from
one. The synthesis of membrane and cell wall
is quite an accomplishment considering the fact
that many bacteria possess three outer layers:
cytoplasmic membrane, cell wall, and outer membrane.
During cell division, all three of these layers
must be precisely extended in a short period
of time, since production of daughter bacteria
that are the same size and shape as the parent
cell can occur rapidly.

Moreover,
a majority of these new membrane and cell wall
components are manufactured preferentially near
the dividing point of the parent cell and are
coordinated with constriction of the cell at
the same location. The cytokinesis process also
accurately partitions the DNA into each daughter
cell, before the division of bacteria is completed.
The DNA segregation mechanism is incredibly accurate,
resulting in correct partitioning of the DNA
greater than 99.9% of the time (Vinella, 1995).

The
initiation of cytokinesis centers around a region
on the membrane that will eventually become the
dividing plane of the cell or the septum. Studies
involving E.coli suggest that the septum
is derived from a site on the membrane called
the periseptal annulus. The periseptal annulus
is a ring that encircles the cell and appears
to be the result of an invagination or a melding
of the inner membrane and the cell wall. The
septum forms near this ring exactly at mid-cell.
(It is unknown how the cell precisely measures
the exact center of the cell.) Several proteins
involved in septum formation form a complex at
this site, working together to form a constriction
ring, synthesize new membrane and cell wall,
and break old membrane and wall attachments.

One
of the earliest acting and most crucial proteins
involved at this site is the FtsZ protein. The
FtsZ protein self-polymerizes and is the primary
component of a division ring that is hypothesized
to constrict during cytokinesis. Upon completion
of the septum, FtsZ depolymerizes. There is strong
evidence to suggest that FtsZ is an essential
cell division factor for free-living bacteria
(Vincente and Errington, 1996). (Bacteria are
considered to be free-living if they are capable
of independent life free from a host organism
or do not require complex nutritional factors
that are typically supplied by the host organism.)
The role of FtsZ in cell division is supported
by the fact that it has been found in bacteria
as diverse as mycobacteria and archaebacteria
(Baumann and Jackson, 1996). Some studies report
that it has some structural and functional similarities
to the cytoskeletal proteins found in eukaryotes
(Vincente and Errington, 1996). It also has the
ability to self-polymerize into strands and cyclic
structures in vitro (Erickson, 1996). The FtsZ
protein concentration is regulated at the level
of transcription and its concentration is estimated
to be between 5000 and 20,000 molecules per cell.
Some studies have suggested that the concentration
of FtsZ fluctuates with the cell cycle and its
concentration can change by as much as 50 percent.

Recent
studies are uncovering a fascinating story about
the biology of the FtsZ protein. The data show
that FtsZ is regulated both temporally and spatially
by transcription and inhibitor proteins. Most
of the data for this system has been derived
from studies of E.coli. The precise regulation
of FtsZ is supported by several studies showing
that a critical amount of FtsZ is needed for
cell division, and that its overproduction or
underproduction can cause cell division anomalies
and affect viability (Lutkenhaus, 1993).

Letís
examine some of the proteins with which FtsZ
interacts, several of which are located on the
cell membrane at the mid-cell septum. Two proteins
located at the E.coli septum, ZipA and
FtsA, are required for proper FtsZ function and
may be directly involved in regulating its actions
(Ma, 1996). For instance, a regulatory role for
FtsA is supported by the fact that a certain
ratio of FtsZ/FtsA is required for cytokinesis
to proceed. Any deviation from the critical FtsZ/FtsA
ratio causes inhibition or alteration of cytokinesis.

There
are several hypothetical models for how FtsZ
could act to constrict the cell at the septum
(Figure 4). One of the more intriguing aspects
of FtsZ biology involves how it preferentially
forms the constriction ring at the mid-cell septum.
FtsZ has several other septal site choices for
binding because multiple binding sites are present
in a single bacterium. For instance, in a pre-division
mother cell, new periseptal annuli are predicted
to form very early on either side of the original
annuli and are eventually placed at one quarter
the length of the cell on each side of the mid-cell
septum. These potential FtsZ binding sites will
form the mid-cell septa in the newly formed daughter
bacteria (see Figure 5). In addition, there are
septum binding sites at the poles of the bacteria,
since the poles were derived from septa from
earlier cell divisions (see Figure 6).

Figure
4. Two hypothetical models for how FtsZ could
act at the septum. FtsZ is known to self-polymerize
in vitro, forming rings and filaments. In the
depolymerization model, FtsZ constricts the cell
by polymerization-depolymerization cycles. In
the sliding protofilament model, FtsZ protofilaments
slide past one another. (Redrawn from Figure
8, Bramhill, 1997.)

Figure
5. Derivation of the septum and periseptal
annuli. The periseptal annulus, which is formed
when the cytoplasmic membrane and the cell wall
meld together, forms a ring around the cell precisely
in the middle of the cell. It is hypothesized
that the annulus serves as a site for development
of the septum. New periseptal annuli have been
detected forming very early in the life cycle
of the bacterium and move away from the center
annulus as the cell grows. They move to a position
mid-way between the cell pole and the mid-cell
annulus. They are then in position to serve as
the mid-cell annulus of the newborn daughter
bacteria.

Figure
6. FtsZ is directed to the mid-cell septum
by the combined actions of several proteins.
Each bacterium has several septum locations where
FtsZ can bind. Both poles of the bacteria contain
septum complexes, since they were derived from
mid-cell septa from their mother bacteria. FtsZ
is directed toward the mid-cell septum region
by the combined action of the MinC, D, and E
proteins. The MinCD protein complex inhibits
FtsZ binding at the poles and MinE overrides
the inhibition at the mid-cell septum, allowing
FtsZ to bind and polymerize. It is not known
how MinE chooses the mid-cell septum.

How
does the FtsZ protein discriminate between these
sites? It is now believed that a set of proteins
generated from a single genetic locus, the MinB
locus, are involved in directing the FtsZ protein
to the mid-cell septum. Three proteins from MinC,
MinD, and MinE genes work together to inhibit
cell division at the cell poles and promote it
at the mid-cell septum. The data and current
models show that the MinC and D proteins act
together as an inhibitor and prevent the FtsZ
protein from acting at any septal site. The MinE
protein counteracts the effects of the MinC and
D proteins precisely at the mid-cell, allowing
the FtsZ protein to bind and polymerize there
(see Figure 6). Apparently it is the ratio of
MinE to MinCD that is important, since any deviation
from an optimal MinCD/MinE ratio causes aberrant
cell division. So, remarkably, FtsZ is controlled
by the spatial concentration of Min proteins
(Lewin, 1997).

Letís
consider the possibility that FtsZ and the Min
proteins could have formed through natural selection.
How does natural selection, using the random,
uncontrolled division processes of the protocell,
promote a cell division system that requires
precise amounts of several essential factors
in the right location at the right time? What
is the selection pressure? Consider the FtsA,
FtsZ, and Min proteins: each protein is a required
component of the cytokinesis process; if one
factor is missing, the cell does not divide properly.
In fact, if the concentration of the factors
is altered, cell division and cell viability
are affected. Therefore, if evolution of all
of the factors does not occur simultaneously,
each factor alone could be a liability to the
cell rather than an asset. If each of the factors
alone is deleterious to life, then the evolution
of each individual factor is less probable, since
the cell lineage harboring the factor would tend
to die out.

For
instance, consider the scenario whereby evolution
of the MinC, D, and E proteins occurred before
evolution of FtsZ. Since it appears that one
of the primary functions of the MinCDE system
is to control FtsZ, what do the MinCDE proteins
do after they evolve? We can postulate that the
MinCDE proteins would be quite useless or even
deleterious in the cell without the presence
of FtsZ unless they were originally selected
to perform another function.

Alternately,
what if FtsZ evolved first? This seems more likely
since FtsZ seems to be essential in all free-living
bacteria. However, our current understanding
is that FtsZ requires several binding proteins
and the MinCDE system to successfully promote
cell division at the mid-cell septum. Without
the MinCDE proteins present in the cell, FtsZ
will polymerize at the poles of the cell and
cause the formation of anucleate mini-bacteria,
diminishing the propagation of the cell lineage.
This is supported by studies which have shown
that if the FtsZ concentration is elevated in
bacteria, it can overcome the MinCD mediated
suppression of septation at the poles of the
cell, and aberrant division can begin at several
septal sites in the cell.

If
FtsZ by itself has a negative or lethal effect
on the propagation of cell lineages, could it
have evolved in a dormant state before the evolution
of its required co-factors? If so, what is the
selection pressure that promotes the evolution
of a dormant or inhibited FtsZ factor? The scientific
evidence points to the fact that a MinCDE or
equivalent system is required for FtsZ to function
properly and supports the hypothesis that many
factors would have to evolve rapidly and simultaneously
for FtsZ-dependent cytokinesis to proceed. This
seems to violate the basic tenants of Darwinian
gradualism. Even if the MinCDE and FtsZ factors
could have co-evolved we are still left with
questions involving how the MinCDE system can
select the mid-cell septum and how regulation
of FtsZ polymerization occurs.

The
fact that FtsZ requires several protein factors
that work in a precise interdependent fashion
to promote cytokinesis shows that the FtsZ-dependent
cytokinesis mechanism present in E.coli
is an irreducibly complex system. As such, it
is highly questionable whether this complicated
system could have arisen by Darwinian gradualism
starting with a simple protocell.

Evidence
for a Darwinian process in the late protocell

Since
it appears that it is unlikely that the MinCDE-FtsA-FtsZ-dependent
cytokinesis apparatus found in E.coli
could have existed in the early protocell, a
biologist committed to philosophical naturalism
could postulate that such a system may have evolved
in the prebiotic soup, or else in the more stable
late protocell.

First,
letís consider the derivation of the system by
a gradual mechanism in the pre-biotic soup. This
seems even more unlikely than its derivation
in the early protocell. For instance, how could
spatial control be achieved in the vast oceans
of the prebiotic soup? Dilution would certainly
be a problem. In addition, there is no membrane
to divide, which is the primary reason for selecting
such a system. Once again we can conclude that
the spatial and temporal control of several factors
involved in cytokinesis represents, at least
in E.coli, a complex system that is difficult
to account for by any gradualist theory.

By
contrast, there is data that may support the
evolution of the FtsZ-dependent cytokinesis system
in the late protocell. For instance, even though
the FtsZ protein is highly conserved, several
bacteria lack some of the proteins that are part
of the FtsZ-dependent cytokinesis system (see
Table 1). Could these bacteria represent cells
that have evolved only part of the FtsZ-dependent
cytokinesis system or a simpler form of the system?
Could these bacteria thus be close descendants
of the late protocell?

There
is a one major problem with this suggestion.
Proteins can be identified either by their function
or by their amino acid sequence. Most of the
missing cytokinesis proteins in these bacteria
have been determined to be missing because their
amino acid sequence is not found. But it is possible
that a different protein is fulfilling the same
role as the missing protein. For instance, the
amino acid sequence of the MinE protein is not
found in the bacterium Bacillus subtilis,
but a protein designated DivIVA has been detected
that fulfills the role of the MinE protein (Boche
and Pichoff, 1998). Therefore, in B.subtilis
the cytokinesis apparatus appears to be irreducibly
complex even though it lacks MinE.

Using
the Intelligent Design model, we could predict
that since an irreducibly complex FtsZ-dependent
cytokinesis mechanism exists in E.coli
and B.subtilis, and since it appears to
be essential to bacterial life, a similar system
may exist in all bacteria. The components of
the system could be different structurally but
their functions would be the same or similar.
At this point, however, since all the components
have not been identified in all bacteria, all
we can conclude is that the cytokinesis apparatus
of E.coli fits the definition of an irreducibly
complex system.

Since
the complete genomes of several bacteria are
known, it would be interesting to analyze these
genomes by sequence analysis for the presence
of components of the FtsZ-dependent cytokinesis
apparatus. This would allow us to begin to determine
which components exist and which have yet to
be identified. This analysis would also help
determine the minimal requirements needed for
a cytokinesis apparatus and would represent a
first step toward elucidating whether a simple
or even non-irreducibly complex cytokinesis system
exists.

Evidence
from amino acid sequences

FtsZ
has been detected in all free-living bacteria
analyzed for its presence. Based on data derived
from the study of E.coli we will hypothesize
that the proteins FtsZ, FtsA, MinC, MinD, and
MinE/DivIVA represent a core cytokinesis apparatus.
Table 1 shows which of these proteins have been
detected by amino acid sequence analysis in the
thirteen free-living bacteria whose complete
genomes have been determined. Five of the thirteen
bacteria species possess a full complement of
these proteins. In the others, one or more of
the proteins are missing. It is interesting to
note that at least one Min protein is present
with FtsZ in all the bacterial species. Could
some of the Min proteins perform multiple roles,
or is one Min protein sufficient? We could argue
that perhaps the combination of FtsZ, one binding
protein, and one septum-locator protein like
MinE, represents a minimal irreducibly complex
cytokinesis apparatus in bacteria. At least,
so far the evidence points toward this conclusion.
However some bacteria like mycoplasma, which
often require a host cell and complex growth
requirements, appear to be missing the amino
acid sequence for a majority of these factors.
Therefore, until all bacteria are analyzed, and
cytokinesis proteins detected, we cannot make
the claim that an irreducibly complex cytokinesis
system is a universal phenomena in all free-living
bacteria.

Even
though a universal system has not yet been detected,
genome analysis has revealed that the FtsZ protein
itself is an important universal cytokinesis
protein because it is found in all free-living
and many non-free-living bacteria. This is intriguing
because non-free-living bacteria, such as the
mycoplasmas, often borrow proteins or energy
from the host cell to survive and therefore they
tend to have smaller genomes and fewer proteins,
and yet mycoplasma possesses the FtsZ protein.
However, Chlamydia trachomatis, a parasitic
bacterium which requires another cell in order
to grow and divide, is the first bacterium in
which the FtsZ amino acid sequence has not been
detected (Stephens et al., 1998). Even more interesting,
the FtsA and MinD genes have been located in
chlamydia. Could chlamydia harbor a cell division
system that is FtsZ-independent, or a
simpler cell division system? Could it even represent
a transitional bacterium that has evolved only
part of the cytokinesis apparatus?

Possibly.
However, there is data to suggest that chlamydia
use a complicated cell division mechanism and
probably divide using a division ring like FtsZ.
In fact, there are three lines of evidence supporting
this. One line of evidence shows that chlamydia
possess a cell division protein called cytoplasmic
axial filament protein (cafa). This protein has
been shown to be essential to division in some
bacteria and may form filaments similar to FtsZ
(Okada et al., 1994). Therefore, cafa could replace
FtsZ. Second, non-free-living bacteria like chlamydia
have been found to recruit cytoskeletal components
from the cell they parasitize. One researcher
suggests that the recruitment of cytoskeletal
components could allow the bacteria to use the
host cell proteins for stress fibers and cleavage
rings (Rhee and Sanger, 1994; and Sanger, 1999).
It is possible that chlamydia could operate in
this manner. Third, cell division of chlamydia
is affected (the cells increase in size) when
the cells are exposed to cytoskeletal disrupting
agents, suggesting that a cytoskeletal component
is involved in division (Schramm and Wyrick,
1995). At this point, we will have to wait and
see if other cytokinesis components will be discovered
in chlamydia.

It
also appears from sequence analysis that, in
general, parasitic bacteria with small genomes,
like mycoplasma, possess fewer of the core cytokinesis
protein factors. However, it is also interesting
to note that in the bacteria Aquifex aeolicus
and Thermotoga maritima, two of the free-living
bacteria considered by evolutionists to be the
most ancient, an almost-full complement of the
core cytokinesis factors are found (see Table
1). In fact, all the factors are found in Aquifex
which has a genome one-third the size of E.coli.

Speculative
model for FtsZ

FtsZ
is speculated to play a wider role than just
formation of the septum. For instance, it may
play an important role in the timing of cytokinesis.
If FtsZ has other functions and regulates other
aspects of cell division, this would support
the theory that it (or cytoskeletal proteins
like it) may be essential to cell division.

To
understand how FtsZ could play diverse roles
in cell division we could speculate how it might
regulate the timing of cell division with an
increase in cell mass. We could hypothesize that
daughter bacteria receive enough MinCD protein
from the parent to maintain inhibition of division
at all the septal sites of the cell. As the cell
mass increases, so the does the concentration
of FtsZ until it reaches its critical concentration.
Since FtsZ is synthesized at a different rate
from MinCD or FtsA, the correct ratio of FtsZ
with these factors is eventually reached. This
is supported by experimental evidence showing
that cell division does not proceed unless FtsZ
is in a certain proportion with MinCDE and FtsA.
Once the required ratios are achieved, FtsZ polymerizes
and, in coordination with MinE, causes formation
of the division ring at the mid-cell septum.

This
model is intriguing since it suggests a way in
which mass could regulate division. However,
it reveals nothing about how the division factors
evolved; in fact, the model supports the contention
that cytokinesis is a complex procedure involving
many interdependent factors. In addition, the
model does not yet account for how MinE actually
promotes selection of the mid-cell septum. What
it does imply, however, is that FtsZ could have
diverse activities. This is supported by the
fact that FtsZ works with several factors in
addition to the ones we have mentioned. For instance,
there are a number of factors in addition to
FtsA and ZipA that operate at the mid-cell septum
during cytokinesis and we will consider these
next.

Several
studies have shown that septum formation involves
the coordinated interaction of several proteins
for the production of new membrane and cell wall
components (Bramhill, 1997). FtsZ is thought
to interact with several of these proteins at
the septum and is hypothesized to activate those
involved in membrane and cell wall synthesis.
Figure 7 shows the proteins known to be involved
at the septum and their possible arrangement
in the membrane. The number of components required
and the functions that must be performed at the
septum is impressive. The functions of the proteins
and other factors required for cytokinesis are
listed in Table 2. Many are critical to cell
division and cellular life. The requirement of
these factors and their regulation provides more
evidence in support of the hypothesis that in
E.coli and perhaps other bacteria, cytokinesis
is an irreducibly complex system.

Figure
7. Proteins present at the mid-cell septum
in some bacteria. FtsZ works in conjunction with
several proteins at this site on the cytoplasmic
membrane. FtsA and ZipA have been shown to be
required for FtsZ function in E.coli. The Penicillin
binding proteins (PBP) work together to synthesize
cell wall components. The functions of several
other proteins are described in Table 2. (Based
on Figure 8, Bramhill, 1997.)

But
FtsZ-dependent cell septum formation is not the
only complex process involved in cytokinesis.
Another remarkable process that occurs is the
precise partitioning of DNA chromosomes to the
new daughter bacteria. This is also known to
be an active process dependent on several critical
protein factors.

Gene
or site

Protein
name and/or action

FtsZ

Essential
cytoskeletal component

FtsA

Essential
for FtsZ activity in E.coli, binds ATP

FtsK

Present
at septum, may be involved in DNA segregation

FtsL

Transmembrane
coordination

FtsN

Essential
for division, periplasmic action

FtsQ

Periplasmic
action at septum

FtsW

Located
at septum PBP3 activator?

ZipA

Essential
for FtsZ activity in E.coli, may be an anchor

PBP1b

Transpeptidase
activity at septum

PBP3

Penicillin-binding
protein, Division specific transpeptidase
(FtsI)

Slt

Lytic
transglycolase

MinC

Division
inhibitor

MinD

Enhances
MinC inhibition activity

MinE

Site
selection factor for MinC,D

SdiA

Transcription
factor, activates FtsZ transcription

DnaK

Chaperone
(HSP70)

GyrA
GyrB

DNA
gyrases, unwind DNA

TopC
TopE

Topoisomerase
IV, decatenates the chromosomes after DNA
replication.

XerC
XerD

Recombinases
that ensure fidelity of DNA recombination
during DNA replication

MukB

Essential
cytoskeletal protein involved in chro mosome
partitioning

SpoOJ
ParB

Proteins
involved in chromosome partitioning

Table
2. Several of the proteins involved in cytokinesis

Partitioning
of DNA during cytokinesis

As
we have noted, both monoploidy and polyploidy
are likely karyotypic outcomes of early protocell
evolution. Since monoploidy is the dominant form
of genome structure found in contemporary bacteria,
the protocell theory must eventually account
for the dominance of the monoploid state in bacteria.
Furthermore, in contemporary bacteria the monoploid
state is not achieved by random partition processes
but is postulated to involve an elaborate protein-dependent
mechanism that results in accurate partitioning
of DNA chromosomes greater than 99.9 percent
of the time under optimal conditions. Recent
evidence provides a remarkable picture of how
this protein-driven partitioning mechanism is
involved in specifically segregating bacterial
DNA strands or chromosomes.

Three
major problems must be solved by the partitioning
mechanism if the DNA chromosomes are to be accurately
distributed. (1) The circular DNA strands must
be decatenated after DNA replication. Decatenation
involves the unlinking of two circular DNA chromosomes
that are catenated, which means they are linked
together like two links of chain. (2) Once DNA
is decatenated, there must be a mechanism to
separate the strands and direct them to opposite
poles of the mother cell. (3) The decatenation
and separation of the DNA must occur before the
septum wall forms and the daughter bacteria separate.
Recent studies show that all three of these problems
are overcome by an active protein-dependent partition
process involving several proteins.

The
partitioning process has been observed to begin
soon after DNA replication initiation in both
B.subtilis and E.coli (Levin and
Grossman, 1998). The data supporting a partitioning
process that begins very early in the cell cycle
comes from the study of newborn daughter bacteria
that have inherited a partially replicated DNA
chromosome bearing two DNA replication origins.
Using fluorescent tags attached to the origin
regions, researchers have been able to observe
the two replication origins being actively pulled
apart, each toward a cell pole. As the cell cycle
proceeds, the DNA finishes replication, is decatenated,
and each new DNA strand moves towards its origin
(see Figure 8). Each new daughter DNA then begins
replication again in the mother cell before the
completion of cytokinesis. The new replication
origins are eventually polarized on each newly
copied DNA strand such that one origin is directed
toward the pole and one toward the forming septum
of the mother cell (see Figure 8). When the cell
divides, the two new daughter bacteria look similar
to the parent cell, with the replication origins
of the DNA oriented toward the poles of the newborn
cell. In B.subtilis this partitioning
phenomena is dependent on a protein produced
by a gene called SpoOJ (Levin and Grossman, 1998).
Mutations in SpoOJ can cause the formation of
anucleate bacteria. SpoOJ protein is associated
with the origin site on the DNA. It is postulated
that SpoOJ could operate like a tether that actively
segregates the DNA replication origins.

Figure
8. Active partitioning of the bacterial chromosome
before completion of cytokinesis. DNA replication
can occur very early in the cell cycle. The filled
circles in the diagram represent proteins that
have been observed binding on the DNA near the
replication origin. (a) Researchers have noted
that the origins are actively polarized toward
opposite ends of the cell by a protein-dependent
mechanism. (b) As the cell grows a septum begins
to form and FtsZ begins to polymerize at mid-cell.
(c) DNA replication is completed but begins again
on each new DNA. (d) The replication origins
are once again polarized by an active protein-dependent
process such that each new daughter cell receives
a single, partially replicated DNA chromosome
with origins that are polarized towards the cell
poles. (Drawing is adapted from Levin and Grossman,
1998.) A similar figure is available for viewing
on the Internet in an animated form at http://www.cedarville.edu/dept/sm/jwf/division.htm.

This
protein-dependent segregation mechanism has also
been confirmed to exist in both Caulobacter
crescentus and E.coli. A protein similar
to SpoOJ has been identified in C. crescentus
but has not been yet identified in E.coli.
However, motor proteins that are involved in
chromosome partitioning have been identified
in E.coli and B.subtilis (Hiraga,
1993). In E.coli a protein produced by
the mukB gene has been identified as a filamentous
motor protein that binds to DNA (Figure 9). It
is hypothesized that mukB may act like a cytoskeletal
protein that actively moves the DNA, causing
it to move toward the pole towards which the
origin binding protein has been directed. The
role of mukB in partitioning has been confirmed
by observing bacteria with mutant mukB genes.
The mutant bacteria frequently divide abnormally,
producing anucleate bacteria and bacteria with
two copies of DNA.

Figure
9. MukB protein. Drawing of the putative structure
of the mukB motor protein. Each protein is made
of several protein filaments and globular heads.
The middle hinge region may allow mukB to bend.
MukB is involved in the partitioning and packing
of the bacterial chromosome during cell division.
MukB has binding sites for both FtsZ and DNA.
(Redrawn from Figure 1, Hiraga, 1993.)

Curiously,
FtsZ mutants produce similar defects, suggesting
that both FtZ and mukB protein may both be involved
in partitioning. In fact, recent studies have
shown that mukB can bind to FtsZ (Lockhart and
Kendrick-Jones, 1998). These data suggest the
exciting possibility that these proteins may
interact to coordinate chromosome partitioning.
Perhaps the relationship between mukB and FtsZ
could account for the apparent coordination between
septation and partitioning, by insuring that
segregation occurs before septation. Thus, it
appears that mukB and proteins like it could
be another essential part of an irreducibly complex
FtsZ-cytokinesis mechanism.

MukB
is also known to act with several other proteins
to package the DNA (Hiraga, 1993). This sounds
like a simple feat but actually is a remarkable
accomplishment, considering that the DNA is approximately
1000 times longer than the bacterium itself.
In fact, each long circular DNA is packaged in
a highly condensed state called the nucleoid.
This means the cell must untangle and decantenate
two very long rings of DNA, which involves untangling
molecules that potentially have 200 or more folds
(Dillon, 1981). The decatenation process involves
topoisomerases that specifically perform the
final separation process (see Figure 10). Additional
proteins then participate in folding the DNA
into its highly condensed nucleoid state so it
can be packaged in the new daughter bacteria.
Without the packaging proteins and the topoisomerases,
the nucleoids do not separate, which can prevent
cell division.

Figure
10. Decatentation of the replicated bacterial
chromosomes by topoisomerases. After DNA is replicated,
it is in a double-ringed, interlocked (catenated)
form. There are several topoisomerases in the
bacterial cell that maintain chromosome structure.
In the case of decatenation, Topoisomerases IV
binds to one of the DNA rings, cuts it, and allows
passage of the other ring through.

Decatenation
of the DNA rings may not be considered as complicated
as some of the other processes, yet it is one
of the most critical events of cytokinesis. If
the DNA does not separate, production of two
new daughter bacteria will not occur. Furthermore,
imagine the tremendous potential for error involved
in decatenation of DNA in a polyploid protocell.
The problem of handling circular DNA was highlighted
recently in a speculative review paper on microbial
evolution, in which the authors challenge current
dogma and claim that eukaryotes most likely evolved
before prokaryotes, because eukaryotes
have a much more unsophisticated system for replicating
their genomes (primarily because the eukaryotic
genome is linear and not circular) (Pennisi,
1998; and Jeffares, 1998).

Adding
to the complexity of chromosome partitioning
is the finding that bacterial DNA is maintained
in a specific condensed arrangement in the nucleoid.
The condensed state of the nucleoid is maintained
by several protein factors, some of which are
essential to bacterial life (see Table 3). In
fact, studies are revealing that the nucleoid
has a specific complex arrangement with the cell
membrane. The interaction between the membrane
and nucleoid structure is thought to create a
channel-like substructure environment that harbors
multi-enzyme complexes and even controls insertion
of proteins into the membrane. A group of investigators
are proposing that this complex substructure
or ìenzoskeletonî is a necessary organelle-like
structure that is essential to bacterial life
(Norris et al., 1996). Several other studies
have shown that the interaction of factors that
form the nucleoid enzoskeleton are essential
to maintain its shape and may regulate transcription.
Thus the nucleoid and its associated factors
represent another potentially irreducibly complex
system.

Promotes
condensation of nucleoid and may control
binding of other factors like gyrase.

SeqA

Proteins
involved in sequestering the origin of replication
HobH and preventing multiple re-initiations

Gyrase

Topoisomerase
that induces negative supercoils

FIS

Protein
that binds to nucleoid and may help it maintain
its structure

Table
3. Some of the proteins involved in maintenance
of the nucleoid.

Conclusion

We
have explored several basic and essential processes
involved in bacterial cell division. It seems
warranted to conclude that in some bacteria,
both DNA replication and cytokinesis are irreducibly
complex. The presence of these complex systems
in bacteriaóconsidered by many scientists to
be ìliving fossilsîóraises questions about the
gradual derivation of such systems in the pre-biotic
soup or the early protocell. Although the triggers
and global regulators for these cell division
processes have not been elucidated, intriguing
new evidence shows the existence of factors coordinating
activities such as DNA replication and cytokinesis.
For instance, a ìresponse regulatorî protein
called CtrA has been shown to regulate the cell
cycle in C.crescentus by coordinating
DNA replication with cell division. CtrA , a
transcription factor, modulates the transcription
of several cell-cycle promoters. Fascinatingly,
CtrA is itself subject to temporal and spatial
control by both phosphorylation and proteolysis
(Shapiro, 1997). The presence of coordinating
factors in bacteria like CtrA supports the idea
that bacterial cell division is irreducibly complex.

In
summary:

Bacterial
cell division appears to be irreducibly complex.
There is evidence to suggest that it involves
multiple factors that are coordinated to interact
precisely with one another. For instance, it
appears that the complex processes of DNA replication,
transcription, translation, cytokinesis, and
chromosome partitioning are interdependent
and precisely coordinated during cell division.

The
FtsZ-dependent cytokinesis apparatus in E.coli
fits the definition of an irreducibly complex
system because it involves several co-dependent
parts that work together like a machine. If
any single part is eliminated, or its concentration
altered, cell division ceases or is aberrant.
Therefore, we can say that the gradual derivation
of this system by natural selection acting
on a simple protocell is unlikely.

Scientific
evidence gathered from the study of several
free-living bacteria suggest the existence
of a common core cytokinesis system. The core
system consists of a division ring protein,
a protein that directs the division ring to
the mid-cell septum, and a protein that helps
bind the division ring to the mid-cell septum.
In addition, we can speculate that a protein
that partitions DNA strands may also be a part
of this mechanism.

Genome
analysis has revealed that some bacteria do
not possess all the same proteins that are
present in the FtsZ-dependent cytokinesis apparatus
of E.coli. Therefore, a simpler, non-irreducibly
complex apparatus may exist in these bacteria.
Alternately, a complex apparatus may exist,
because all the factors for cell division have
yet to be discovered by functional analysis.

It
is clear from these conclusions that cell division
is not a trivial or simple biological mechanism.
It will be exciting to see if an irreducibly
complex cytokinesis apparatus is universal among
bacteria. The existence of a universal irreducibly
complex cytokinesis mechanism would challenge
the validity of the protocell theory. Because
cell division is a complex mechanism in many
bacteria, it is reasonable to assume that even,
in chlamydia and mycoplasma, a cytokinesis system
exists and that it is irreducibly complex. The
existence of several different kinds of irreducibly
complex cytokinesis apparatuses (e.g., one that
is FtsZ-independent) would be even more problematic
for protocell theorists to explain. Future studies
that focus on identifying cytokinesis factors
by functional analysis will be very helpful in
determining the nature of the complexity of this
process. For instance, analysis of chlamydia
for the presence of an endogenous FtsZ-like protein,
or one recruited from the host cell, will help
determine if a division ring protein is essential
for division.

Acknowledgments:
This project was supported by awards from the
Faculty Summer Scholarship Program and the Computer
Services Faculty Incentive Fund at Cedarville
College.

NOTES:

1.
The focus of this paper is on the ability of
biopolymers (proteins and nucleic acids) and
bio-synthetic pathways to work together in a
coordinated fashion to create the intricate clockwork-like
conditions that promote cell division. I do not
address the question of whether these biopolymers
themselves could have originated by a gradualistic,
evolutionary process in a prebiotic soup. This
problem has been addressed in several reviews
(Swee-Eng, 1996, and Mills, 1996).

Ma,
X. et al. ìColocalization of cell division proteins
FtsZ and FtsA to cytoskeletal structures in living
Escherichia coli bacteria by using green fluorescent
protein.î Proceeding of the National Academy
of Science 93 (1996):12998-13003.

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